Compositions and Kits of Parts Comprising N,N-Dimethyltryptamine and Harmine and Their Use in Therapy

Abstract

The invention relates to a kit of parts comprising N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and harmine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Also provided is a composition comprising N,N-dimethyltryptamine fumarate and harmine hydrochloride. Further, the invention relates to a pharmaceutical composition comprising N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and harmine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Claims

1. A kit of parts comprising: (a) N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (b) harmine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. A composition comprising N,N-dimethyltryptamine fumarate and harmine hydrochloride.

3. A pharmaceutical composition comprising: (a) N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (b) harmine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. The kit of parts according to claim 1 or the pharmaceutical composition of claim 3, wherein (a) is N,N-dimethyltryptamine fumarate and a pharmaceutically acceptable carrier.

5. The kit of parts according to claim 1 or 4, or the pharmaceutical composition of claim 3 or 4, wherein (b) is harmine hydrochloride and a pharmaceutically acceptable carrier.

6. The kit of parts according to any one of claim 1, 4 or 5, or the kit of parts of any one of claim 3, 4 or 5, for use as a medicament.

7. The kit of parts for use or the pharmaceutical composition for use according to claim 6, for use in treating a psychiatric, psychosomatic or somatic disorder.

8. The kit of parts for use or the pharmaceutical composition for use according to claim 6 or 7, wherein the psychiatric disorder is depression, stress-related affective disorder, major depressive disorder, dysthymia, treatment-resistant depression, burnout, anxiety, post-traumatic stress disorder, addiction, eating disorder, or obsessive-compulsive disorder.

9. The kit of parts for use or the pharmaceutical composition for use according to any one of claims 6 to 8, wherein (a) and (b) are not to be administered perorally.

10. The kit of parts for use or the pharmaceutical composition for use according to any one of claims 6 to 9, wherein (a) and (b) are to be administered simultaneously or sequentially.

11. The kit of parts for use or the pharmaceutical composition for use according to any one of claims 6 to 10, wherein (a) is to be administered intranasally.

12. The kit of parts for use or the pharmaceutical composition for use according to any one of claims 6 to 11, wherein (a) is to be administered in a dose of between 10 mg to 100 mg of N,N-dimethyltryptamine per administration, preferably in an incremental manner over a period of time of between 60 to 180 minutes.

13. The kit of parts or the pharmaceutical composition for use according to any one of claims 6 to 12, wherein (b) is to be administered buccally and/or sublingually.

14. The kit of parts for use or the pharmaceutical composition for use according to any one of claims 6 to 13, wherein (b) is to be administered in a dose of between 75 mg to 300 mg of harmine per administration.

15. The kit of parts for use or the pharmaceutical composition for use according to any one of claims 6 to 14, wherein the administration of (b) is to be followed by the administration of (a).

Description

BRIEF DESCRIPTION OF FIGURES

[0145] FIG. 1 shows PK profiles of harmine and DMT, when given both orally (single administration; upper panel; day 1) or when harmine is given buccally with incremental intranasal DMT application (lower panel; day 3).

[0146] FIG. 2 depicts representative PK profiles of an extensive metabolizer (dotted line) and a poor metabolizer (continuous line) for day 1 (peroral pharmahuasca; upper panel) and day 3 (parenteral pharmahuasca; lower panel).

[0147] FIG. 3 shows subjective intensity and valence (liking) ratings for day 1 (peroral pharmahuasca; part 1) and day 3 (parenteral pharmahuasca; part 2).

[0148] FIG. 4 summarizes undesired side effects ratings during day 1 (peroral pharmahuasca; left panel) and day 3 (parenteral pharmahuasca; right panel).

[0149] FIG. 5 depicts time courses of systolic (circle) and diastolic (triangle) blood pressure, pulse (square) and body temperature (lower panel) during day 1 (peroral pharmahuasca; left panel) and day 3 (parenteral pharmahuasca; right panel).

[0150] FIG. 6A depicts ratings in the altered states of consciousness questionnaire (5D-ASC) during day 1 (peroral pharmahuasca; dotted line) and day 3 (parenteral pharmahuasca; continuous line).

[0151] FIG. 6B depicts subdimensions of the altered states of consciousness questionnaire (5D-ASC) during day 1 (peroral pharmahuasca; dotted line) and day 3 (parenteral pharmahuasca; continuous line).

[0152] FIG. 7 depicts a representative PK profile of a single participant that discontinued intranasal DMT administration at T90 on study day 3, which was followed by an immediate drop in DMT plasma concentrations underscoring the safety and flexibility of sequential dosing.

[0153] FIG. 8 depicts a hypothesized model of the biphasic action of peroral pharmahuasca (upper panel A) with an initial psychedelic phase that is driven by fast DMT absorption into the blood stream. With sequential-incremental DMT administration (parenteral pharmahuasca, lower panel B) the distressing aspects of the initial psychedelic phase (e.g. visual hallucinations, perceptive distortions, derealisation, or confusion) can be attenuated, while preserving the empathogenic-entactogenic effects of the drug (e.g. intensified emotions, enhanced introspection, compassion, affective connectedness), which increases the overall safety and tolerability for psychedelic-assisted therapy in patient populations.

[0154] FIG. 9 depicts comparison of plasma concentrations of harmine and DMT in two subjects—one that responded to treatment with DMT/harmine, and one that did not respond.

[0155] FIG. 10 shows individual responses of subjects administered with peroral pharmahuasca (Part 1 and 2) at different time points of day 1 and day 2 of the study, assessing their experience regarding: A) overall intensity, B) liking of the effects, C) arousal and D) body boundaries. Part 3 of the Figure shows subjective effects with parenteral pharmahuasca in the same study population, assessing their experience regarding overall intensity, liking, arousal, and relaxation at study day 3.

[0156] FIG. 11 depicts side effects as assessed by subjects using peroral pharmahuasca in the course of day 1 of the study, regarding A) nausea, B) somatic distress and C) psychological distress (part 1). The Part 3 of the Figure shows the side effect profile of parenteral pharmahuasca in the same population of subjects at study day 3.

[0157] Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.

[0158] The following examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention which is defined by the appended claims.

EXAMPLES

[0159] Participants and Permission: N=10 healthy male subjects (20-40 years, mean age 30.7±5.4 years; Body Mass Index of between 18.5 and 25) with no current use of drugs or medications, no current or previous history of somatic, neurological or psychiatric disorder and no family history of Axis-I psychiatric disorder were recruited by medical screening. The study was approved by the Cantonal Ethics Committee of the Canton of Zurich (Basec-Nr. 2018-01385) and Swiss Federal Office of Public Health (BAG-Nr. (AB)-8/5-BetmG-2019/009268). All participants provided written informed consent according to the declaration of Helsinki and were monetary compensated for the completion of the study.

[0160] Study setting: The study was conducted during the daytime in soundproof, climatized, and furnished bedrooms to provide a comfortable living room atmosphere with dimmable lights and sound systems. Throughout all study days, a standardized playlist containing non-stimulating background music was played to provide a feeling of comfort and relaxation. An experimenter was present in the room all the time to supervise the participants.

[0161] Study design: In this open-label, dose-finding, pilot study, acute subjective effects and blood samples following the administration of 250 mg harmine with a dose of 30 mg vs. 50 mg of DMT (single peroral administration—Example 1) vs. 150 mg buccal harmine with 50 mg of sequential intranasal DMT administration (Example 2) have been tested. On all study days, harmine was premedicated 30 min prior to DMT administration. As this was a dose-finding study, participants were given preferable dose ranges (e.g. 50 mg for day 3) and could dis-/continue further dose administration within the indicated margins (e.g. 0-5 mg of DMT every 15 mins over 120 mins) to enhance safety and tolerability.

[0162] Blood sampling and analysis: Blood samples for analysis of DMT and harmine concentrations in plasma were collected from the left antecubital vein at −30 (baseline), −15, 0, 15, 30, 45, 60, 75, 90, 120, 180, 240, 300, and 360 min (peroral pharmahuasca study) and at −30 (baseline), −15, 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 180, 240 and 300 min after drug administration (parenteral pharmahuasca study). The venous catheter was connected to Heidelberger plastic tube extensions, to collect blood samples without disturbing the subjects during their psychedelic experience. The intravenous line was kept patent with a slow drip (10 ml/h) of heparinized saline (1000 RJ heparin in 0.9 g NaCl/dL; HEPARIN Bichsel; Bichsel AG, 3800 Unterseen, Switzerland). Blood samples were immediately centrifuged for 10 minutes at 2000 RCF and plasma samples were transferred to Eppendorf tubes, shock-frozen in liquid nitrogen (˜−196° C.) and stored at −80° C. until assay. For analytic purposes, DMT was purchased from Cayman (Ann Arbor, USA), and harmine was purchased from Sigma-Aldrich (St. Louis, USA) and DMT-d6 were purchased from Toronto Research Chemicals (Toronto, Canada). All other used chemicals were of highest grade available. For the sample preparation 200 μl of plasma, 50 μl of the internal standard (IS) (20 ng/ml DMT-d6) and 50 μl of Methanol (MeOH) were added to a tube. Proteins were precipitated by adding 400 μl of acetonitrile (ACN) and samples were shaken for 10 minutes and centrifuged for 5 min at 2000 RCF. 350 μl of the supernatant was further transferred into an auto-sampler vial, evaporated to dryness under a gentle stream of nitrogen and reconstituted with 250 μl of an eluent-mixture (98:2, v/v). Calibrator and quality control (QC) samples were prepared accordingly, replacing the MeOH with calibrator or QC solutions. Samples were analyzed on an ultra-high performance liquid chromatography (UHPLC) system (Thermo Fisher, San Jose, Calif.) coupled to a linear ion trap quadrupole mass spectrometer 5500 (Sciex, Darmstadt, Germany). The mobile phases consisted of a mixture of water (eluent A) and ACN (eluent B), both containing 01% of formic acid (v/v). Using a Kinetex C18 column (100×2.1 mm, 1.7 μm) (Phenomenex, Aschaffenburg, Germany), the flow rate was set to 0.5 mL/min with the following gradient: start conditions 98% of eluent A for 0.8 min, decreasing to 60% within 6.7 min followed by a quick decrease to 8% within 0.1 min. These conditions were held for 0.9 min and switched to the starting conditions for re-equilibration for 0.5 min. The mass spectrometer was operated in positive electrospray ionization mode with scheduled multiple reaction monitoring. The following transitions of precursor ions to product ions were selected: DMT, m/z 189.1->58.2, DMT-D3, m/z, 195.1->64.1, harmine, m/z 213.0->169.2. The concentration range in calibration standards was 0.5 ng/ml to 60 ng/ml for DMT, and 3 ng/ml to 360 ng/ml for harmine. Thus, the lower limit of sensitivity was 0.5 mg/ml for DMT, and 3 ng/ml for harmine.

[0163] Psychometry: The intensity and valence of subjective effects was monitored throughout the study with visual analogue scales (VAS range 0-100 on a touchscreen tablet) at baseline, −15, 0, 15, 30, 45, 60, 90, 120, 180, 240, and 360 min (peroral pharmahuasca study) and at baseline, −15, 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 180, 240, and 300 min after drug administration (parenteral pharmahuasca study). Additionally, the Altered States of Consciousness Rating Scale (5D-ASC) (Studerus et al. 2010) was included. The quantitative psychometric assessments were complemented by semi-structured qualitative interviews that were audio-recorded towards the end of the experimental day with a focus on the phenomenology of what people report about their experience.

[0164] Vital signs and adverse effects: The participants were screened for (serious) adverse effects throughout the experiment by the study physician, including questionnaire-based assessments (visual analogue scales, 0-100 or yes/no) of physical and mental discomfort, breathing difficulties, racing heartbeat, chest or abdominal pains, unpleasant body sensations/muscle pains, headache, nausea, vomiting, and fainting at baseline, 60, 120, 180, and 240 min after drug administration. Vital signs (systolic/diastolic blood pressure, heart rate, body temperature) were monitored throughout the study at −30 (baseline), 30, 90, 150, 210, and 360 min (peroral pharmahuasca study) and at −30 (baseline), 0, 30, 60, 90, 120, 180, 240, and 300 min after drug administration (parenteral pharmahuasca study).

[0165] Study drug: DMT fumarate was obtained as follows: DMT in its basic form was obtained by acidic-basic aqueous extraction from the root bark of Mimosa hostilis (The Mimosa Company, 1069CL Amsterdam, NL), with n-heptane as organic solvent DMT was purified by crystallisation and further recrystallized as DMT fumarate (CAS: 68677-26-9) via salt precipitation. Briefly, DMT in its basic form was dissolved in acetone (9.82 g of DMT free base in 282 mL of acetone). Fumaric acid was also dissolved in acetone (2.89 g fumaric acid in 414 mL acetone). After that, the fumaric acid solution was slowly added to the DMT solution to form the DMT fumarate salt. The solution was left at room temperature for 60 minutes and crystals of the DMT fumarate salt appeared. Excess acetone was decanted, and the crystals of DMT fumarate were washed twice with 100 mL acetone. The DMT fumarate salt was then dried under vacuum. The final product was subjected to qualitative and quantitative analysis via quantitative Nuclear Magnetic Resonance (qNMR), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatography (HPLC), revealing a purity of 98.20%±0.37%. Based on the qNMR analysis (performed by Reseachem GmbH, Burgdorf, Switzerland) the study drug is believed to be characterized by DMT to fumarate ratio of about 2:1 (1:0.497). Harmine hydrochloride (Harmine HCl, ≥98%, CAS 343-27-1; C.sub.13H.sub.12N.sub.2O.Math.HCl; 248.71 g/mol) was procured from Santa Cruz Biotechnology Inc. (Dallas, Tex. 75220, USA).

Example 1. Peroral Pharmahuasca Study (Reference Example)

[0166] Peroral formulation: DMT fumarate (dose for day 1: 30 mg; dose for day 2: 50 mg) was encapsulated into opaque size 0 hydroxypropyl methylcellulose (HPMC; Interdelta S. A. Givisiez, 1762, Switzerland) capsules, whereas mannitol was used as filler. To prolong the duration of MAO inhibition by harmine and thus the half-life of DMT, a harmine formulation with an extended-release (ER) profile was developed. Therefore, 2 types of harmine minitablets were manufactured, either with an immediate release (IR) profile (no retardation) or an extended-release (ER) profile. Then both tablet types were combined in a capsule, to form a combination product, whereas parts of the drug are released immediately (150 mg) and another proportion (100 mg) is released slowly. Harmine IR minitablets were obtained as follows: Harmine HCl was ground and compressed using a Glatt tablet press, to form IR minitablets containing 25 mg of harmine HCl. Harmine ER minitablets were manufactured as follows: Harmine HCl was ground, blended with methocel K and compressed with a Glatt tablet press, to form ER minitablets containing 20 mg harmine HCl. The in vitro dissolution profile was examined according to the European Pharmacopoeia. Harmine minitablets were encapsulated into opaque size 0 HPMC capsules, so that said capsule contained: [0167] 5 Harmine HCl ER minitablets (100 mg of harmine in total)—each minitablet including 20 mg of harmine hydrochloride and methocel K, its diameter being substantially equal to 5 mm. [0168] 6 Harmine HCl IR minitablets (150 mg of harmine in total)—each minitablet including 25 mg of harmine hydrochloride and HPMN, its diameter being substantially equal to 5 mm.

[0169] Dose regimen: During study day 1 and 2, subjects received both harmine and DMT as peroral formulations on empty stomach (last meal >10 hours; last drink >90 mins). 30 minutes following peroral premedication with 250 mg harmine HCl (150 mg immediate release+100 mg extended release), subjects ingested a dose of 30 mg of DMT fumarate on day 1 and 50 mg of DMT fumarate on day 2.

TABLE-US-00001 Dose regimen Day 1/2 - combined oral harmine HCl and oral DMT fumarate administration Time Harmine HCl Harmine HCl [min] IR [mg] ER [mg] DMT fumarate [mg] −30 150 100 — 0 — — 30 (Day 1) vs. 50 (Day 2)

[0170] Pharmacokinetic profile: Based on the PK/PD profiles (see FIGS. 1 and 9), it is assumed that the bioavailability and psychotropic potency of DMT depends on the bioavailability of harmine as a MAO inhibitor. Surprisingly, huge interindividual differences in plasma concentrations of both DMT and harmine were found after a single peroral administration (FIG. 9). Peak plasma concentrations (also referred to as C.sub.max) varied substantially by a factor of about 7 for DMT and by a factor of about 50 for harmine across subjects, and likewise time to peak values (t.sub.max) of harmine ranged from 60 to 270 minutes (see FIGS. 1 and 2). Accordingly, subjective drug effects varied dramatically between subjects (see FIG. 3), with peak intensity ratings ranging from 1 (non-responder) to 10 (responder). This considerable difference in interindividual responsiveness was highly unexpected and raised doubts, whether peroral pharmahuasca would be clinically applicable.

[0171] Harmine is mainly degraded by the hepatic enzyme CYP2D6. Multiple allelic variants of the CYP2D6 gene have been identified, which are associated with a reduced or increased enzyme activity in individuals who are respectively so-called poor (PMs), extensive metabolizers (EMs) and ultrarapid metabolizers (UMs) (Peñas-Lledõ & Llerena, 2014). Thus, depending on an individual's allelic variant of the CYP2D6 gene, the bioavailability of harmine may vary substantially across subjects. Based on the diet recommendations established in the context of traditional ayahuasca ceremonies (e.g. low-tyramine diet) and studies on different metabolism rates (CYP2D6) by harmine, it is concluded that the MAO enzyme activity in the GI tract is subject to considerable inter-individual variability and a reliable standardization of the DMT effect can only be achieved by parenteral administration. The heterogeneity and variability of the transient psychotropic DMT effect following peroral administration necessitates a change in galenic formulation and dosing regimen that produces more robust and sustainable neurobehavioral effects.

[0172] Psychometric assessment: The peroral administration of 250 mg harmine with 30 mg DMT was on average well tolerated. However, the psychotropic effects in comparison to traditional ayahuasca were only transient and significantly less pronounced (4 non-responders without psychotropic effects, 3 partial responders with only short-term DMT effects, 3 responders with typical and briefly overwhelmingly intense DMT effects; FIG. 3). Surprisingly, no marked differences in VAS ratings (e.g. overall intensity, liking, arousal, body boundaries) between oral pharmahuasca with a lower (30 mg) vs. a higher dose (50 mg) of DMT (FIG. 10, Part 1 and 2) were found, which underscores the notion that dose-predictability with oral pharmahuasca is very low. The 5D-ASC assessment of altered states of consciousness revealed that peroral pharmahuasca induces transformative experiences (e.g. oceanic boundlessness and visionary restructuralization) that are considered to mediate symptom reduction according to the literature on the efficacy of psychedelic-assisted therapy. No anxious ego-dissolution or acoustic alterations were observed and levels of vigilance reduction were comparably low (FIG. 6A). Qualitative interviews after the experience (data not shown here) confirmed the quantitative psychometric results.

[0173] Vital signs and undesired side effects: In comparison with previous studies with traditional ayahuasca, a significantly better tolerability with the peroral preparation described herein (e.g. low spectrum of somatic side effects, especially less nausea and no vomiting) has been demonstrated (FIG. 4; FIG. 11, Part 1). In general, the administration of peroral pharmahuasca induced only transient, asymptomatic, and clinically non-significant elevations of cardiovascular parameters and body temperature (FIG. 5), which underscores an overall very good safety profile.

Example 2. Combined Intranasal/Buccal Study (Parenteral Pharmahuasca)

[0174] Intranasal formulation of DMT fumarate: DMT fumarate nasal sprays were manufactured by dissolving DMT fumarate in saline (0.9 g NaCl/dL) with concentration of 2.5 mg of DMT fumarate per hub. The solution was then transferred into nasal spray PUMP systems with a hub volume of 50 μl (Aptar Pharma, 78431 Louveciennes, France). A total of 50 mg DMT with an added 20% excess volume were prepared to avoid aspiration of air and consequently dilution of the administered dose.

TABLE-US-00002 orange DMT fumarate flavour saline (0.9 g NaCl/dL) dose per bottle 50 mg (+20%) 28 mg add 2.8 ml dose per hub 2.5 mg 1.4 mg add 0.14 ml

[0175] Sublingual formulation of harmine hydrochloride: Harmine hydrochloride (harmine HCl) orodispersible tablets were manufactured by freeze-drying a harmine/excipient solution. Therefore, harmine HCl (75 mg) was mixed with purified water, mannitol, HPMC and lemon flavor to yield a clear solution. The solution was then volumetrically dosed into aluminum molds, shock-fozen at −80° C. and lyophilized for 36 hours. The final product (75 mg harmine HCl per unit) was then packaged and stored under dry conditions (in the presence of desiccant bags) and dark conditions at room temperature. This formulation is also suitable for use as buccal formulation.

[0176] Dose regimen: During study day 3, harmine HCl was administered buccally as orodispersible tablet, while DMT fumarate was applied as intranasal spray solution. 30 minutes following sublingual premedication with 150 mg of harmine HCl (subjects were instructed to keep the tablet between lower lip and gingiva and to avoid excessive swallowing), subjects were administered a cumulative dose of up to 50 mg of DMT fumarate according to the table below. On timepoints 45, 60, 75, 90, 105 and 120 volunteers were allowed to dis-/continue further dose administration within the indicated margins (e.g. 0-5 mg of DMT every 15 mins) to enhance safety and tolerability. Only 6 out of 60 flexible DMT administrations (10%) were skipped by the participants.

TABLE-US-00003 Dose regimen Day 3 - combined buccal harmine HCl and intranasal DMT fumarate administration Time [min] Harmine HCl [mg] DMT fumarate [mg] −30 150 — −15 — — 0 — 10 15 — 5 30 — 5 45 — 5 60 — 5 75 — 5 90 — 5 105 — 5 120 — 5 Total 150 50

[0177] Pharmacokinetic profile: By bypassing the GI tract (first pass metabolism, pH dependence of absorption, GI tract motility etc.) with a parenteral preparation, herein intranasal formulation of DMT fumarate and sublingual formulation of harmine hydrochloride, a better standardization of bioavailability, a lower interindividual variance as well as a more reliable dose-response relationship with presumably fewer somatic side effects can be achieved. Analysis of the blood plasma curves following oral and parenteral administration of DMT/harmine underlines this notion. As shown in FIG. 1, the parenteral administration of both DMT fumarate (intranasal) and harmine HCL (buccal) yield substantially higher bioavailability (higher area under the curve; AUC) and more homogenous plasma curves (reduced standard deviations) compared to their oral administration. Peak plasma concentrations (c.sub.max) for extensive vs. poor metabolizers varied by a factor of ˜2.3 for DMT and only a factor of ˜3.2 for harmine across subjects (see FIG. 2). Due to parenteral administration, it is possible to reduce the retarded dose of 250 mg harmine (peroral) to an unretarded dose of 150 mg harmine (buccal) and achieve sufficient CNS inhibition effects. Surprisingly, the buccal delivery of harmine produced a smooth sustained-release profile which is favorable for repeated intermittent dosing of DMT over 120 minutes. Moreover, the time in the therapeutic range (TTR) is significantly longer following the combined intranasal/buccal application of DMT and harmine. Incremental intranasal DMT administration yields a linearly increasing plasma curve with comparably smaller standard deviations, further underlining the superiority of this route of administration compared to the oral route, namely in terms of predictability and reliability. In addition, intranasal DMT administration for dose determination offers a better safety profile due to increased controllability, because DMT doses can be administered incrementally and sequentially. The pharmacological intervention can be interrupted at any time if side effects occur, which is not the case with peroral administration of a retarded DMT preparation. FIG. 7 shows a representative PK profile of a single participant that discontinued intranasal DMT administration at T90, which was followed by an immediate drop in DMT plasma concentrations without affecting subsequent DMT administrations at T105 and T120. This example highlights the flexibility of the intranasal sequential-intermittent DMT dosing regimen for improving the safety in patient populations, given the need to minimize the psychological risks inherent with the use of psychedelic compounds.

[0178] Psychometric assessment: The sublingual administration of 150 mg harmine with 50 mg DMT (intranasally) was very well tolerated (low scores on anxiety, loss of control, disorientation; VAS ratings of “liking” between 70-100 out of 100; see FIG. 3, Part 2 and FIG. 10, Part 3). Compared to the oral route of administration, the psychotropic effects were much more pronounced and sustained, resulting in an improved response predictability (9 out of 10 subjects fully responded until 180 min after DMT administration; see FIG. 3, Part 2). Compared to peroral pharmahuasca, the 5D-ASC ratings revealed higher levels of oceanic boundlessness and visionary restructuralization and lower levels of vigilance reduction with parenteral pharmahuasca (FIG. 6A). On the level of the subscales, an optimized experience profile with higher levels of transformative experiences (e.g. blissful state, experience of unity, and insightfulness) could be achieved, with very low levels of anxiety, disembodiment, or impaired cognition and control (FIG. 6B). Such an experience profile is unique for a psychedelic agent and is presumably related to the optimized galenic of DMT and harmine co-administration (see also FIG. 8). Compared to other psychedelics, parenteral pharmahuasca does not impair cognition and does not induce anxiety or confusion and hence seems to be very well suited to support psychotherapy. Based on qualitative interviews, study participants clearly favored the parenteral over the oral formula. Most importantly, the incremental administration of DMT permitted to shape the dosing regimen according to participant's feedback, making it much more controllable and thus safer to guide the participants through the psychedelic experience. Participants have also noted that the incremental administration of DMT attenuates the initial distressing aspects of the psychedelic experience while preserving the empathogenic properties of the drug which is more favorable for clinical applications in vulnerable patient populations (for details see FIG. 8).

[0179] Vital signs and undesired side effects: Compared to the oral administration, on average less somatic side effects (e.g. nausea, distress) occurred with parenteral administration, indicating a better safety and tolerability profile (FIG. 11, Part 2). While vomiting and diarrhea are common features of traditional ayahuasca, no such cases were observed in our study sample. Further details are shown in FIGS. 4 and 5.